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Human-Mouse Hybrids?
scientistguy writes "There is a remarkable story by Nicholas Wade in the early
morning edition of the New York Times about a discussion to create human-mouse
hybrid organisms. One of these techniques involves the introduction of genetically altered mouse embryonic stem (ES) cells (e.g. with
genes 'knocked-out' or replaced) into a developing mouse blactocyst to create progeny hybrid organisms. Typically, these progeny organisms are then bred to unaltered mice to see
if the genetic alteration has gone germline or is heritable. If heritable, mice can be bred and
animals which are homozygous for the altered gene can be phenotypically examined as long as the manipulation is not homozygous lethal or cause
sterility in a single copy state. Unless using
blastocysts from immunologically crippled mice, there would most likely be a recognition of non-self by murine immune cells not educated (which haven't seen during their development) to the human cells that would wipe them out. Nonetheless, it's amazing that it's
being contemplated due to the ethical implications of such an experiment. What if it were viable? What if there were more than just a few
human cells? Could it be sacrificed? ... or even experimented on further if part 'human'? Perhaps these
types of experiments are best relegated to little known, deserted islands far
away from the reaches of civilization (or perhaps regulation) ..."
Stem Cell Mixing May Form a Human-Mouse Hybrid
By NICHOLAS WADE
A group of American and Canadian biologists is debating whether to recommend stem cell experiments that would involve creating a human-mouse hybrid.
The goal would be to test different lines of human embryonic stem cells for their quality and potential usefulness in treating specific diseases. The best way to do that, some biologists argue, is to see how the cells work in a living animal. For ethical reasons, the test cannot be performed in people.
But if the human stem cells are tested that way in mice, any animals born from the experiment would be chimeras -- organisms that are mixtures of two kinds of cells -- with human cells distributed throughout their body. Though the creatures would probably be mice with a few human cells that obey mouse rules, the outcome of such an experiment cannot be predicted. A mouse with a brain made entirely of human cells would probably discomfort many people, as would a mouse that generated human sperm or eggs.
Dr. Irving L. Weissman, an expert on stem cells at Stanford University, said that making mice with human cells could be "an enormously important experiment," but if conducted carelessly could lead to outcomes that are "too horrible to contemplate." He gave as an extreme example the possibility that a mouse making human sperm might accidentally be allowed to mate with a mouse that had made its eggs from human cells.
At least two biologists in the group that is discussing the experiment said they believed that it was premature or unethical and could stir policy makers to limit further stem cell research or ban it.
Stem cells are a kind of universal clay, so responsive to local cues that they can morph into blood, skin, bone or any other replaceable tissues. They retain the gift of self-renewal, which, to curb the risk of cancer, is withdrawn from all the body's mature cells. Stem cells, when they divide, usually produce one mature cell and one stem cell.
They hold high promise as an all-purpose material for repairing many degenerative diseases of old age like Parkinson's, cancer and heart disease.
Other scientists say such experiments would be of great value and could be conducted with human stem cells engineered so that they could not produce brain or reproductive cells. That group acknowledged that even an experiment drawn up with such precautions should first undergo scientific review and public debate.
The proposal for the experiment grew out of a meeting on Nov. 13 at the New York Academy of Sciences sponsored by the academy and Rockefeller University. It was organized by Dr. Ali H. Brivanlou, a Rockefeller biologist who studies embryology.
Dr. Brivanlou invited eight other experts and, as observers, two editors of scientific journals and Dr. James F. Battey Jr., director of the National Institute of Deafness and chairman of the stem cell task force of the National Institutes of Health. The meeting was not intended to be public, Dr. Brivanlou said, and at one point, the nine experts held a closed session at which the observers, including even Dr. Battey, were asked to step outside.
One journal editor wrote of the meeting in the current issue of Nature, reporting that Dr. Battey "criticized participants for what he regards as excessive secrecy." Dr. Battey did not return telephone calls to his office.
The purpose of the meeting, Dr. Brivanlou said yesterday in an interview, was to discuss quality standards for several new lines, or colonies, of human embryonic stem cells being developed around the world.
In one test that they discussed, human embryonic stem cells would be injected into an early mouse embryo when it was still a small ball of cells called the blastocyst. Scientists would then see whether the human stem cells showed up in all the mouse's tissues. That ability, known as pluripotentiality, is the hallmark of a true embryonic stem cell.
Injection into another mouse's blastocyst is the standard test for mouse embryonic stem cells. Those cells, like human embryonic stem cells, come from a small pool of all-purpose cells a few days after the fertilized egg has started to divide.
(Page 2 of 2)
No one knows whether human embryonic stem cells would survive in a mouse blastocyst. If they did, and they contributed to all the tissues, that would be a useful test for the many claimed human embryonic stem cell lines being developed, Dr. Brivanlou said.
One participant, Dr. Janet Rossant of Mount Sinai Hospital in Toronto, said that she did not consider the test necessary and that if the injected human cells made major contributions to the mouse, "I think that is something that most people would find unacceptable."
Dr. Weissman of Stanford, who was not at the meeting, said the experiment could help scientists follow the behavior of human cells with genetic diseases. Studying how the diseased human cells develop in a mouse could offer treatment insights.
Dr. Weissman said undesirable outcomes like a mouse with a brain made of human cells or a mouse that generated human sperm could be avoided by deleting certain genes from the human cells before injecting them into a mouse. He added that such procedures should be carefully reviewed by a body like the National Academy of Sciences.
"You must assure yourself and the public," he said, "that it's ethical. It's not for scientists alone to decide."
A biologist at the meeting here, Dr. Fred H. Gage of the Salk Institute, said that the question of making mice with human cells deserved further consideration and that scientists and the public "should listen to each other more" before reaching a conclusion to go ahead.
In using mice simply to test the pluripotentiality of human embryonic stem cells, it would not be necessary to let the mice grow to term, Dr. Gage said. The earlier the mice were killed the smaller would be the ethical issue, in his view.
Dr. Richard M. Doerflinger of the National Conference of Catholic Bishops, who has long opposed research with human embyronic stem cells, said his primary objection remained with the first step, that of killing a human embryo to obtain embryonic stem cells. Dr. Doerflinger's initial reaction to the proposed experiment was that as a test for pluripotentiality it might not be objectionable.
"If you end up with one human cell per organ of a mouse, I don't think it raises a new problem," he said. "The amounts of human material in an animal would have to be pretty substantial to start talking about a human hybrid, and I don't think this raises that specter."
The nine participants at the conference are drafting a white paper to lay out proposed standards to test human embryonic stem cells. The mouse injection test is on the list, Dr. Brivanlou said, with the wording under discussion.
Federally financed researchers can work only with "presidential cell lines," the human cell lines established before Aug. 9, 2001, which President Bush declared as the cutoff for permissible stem cell work. The guidelines prepared by Dr. Brivanlou's group could be applied to those stem cells, as well as the nonpresidential ones.
Cheers Google ...
The nation of registry of choice for many ships is currently Liberia. Just think about it the next time you consider going on one of those delightful Disney cruises.
~Idarubicin
Don't be so afraid, the reporter got almost all his facts wrong. There will be 0 (zero) human cells in the chimera. That's not the way this procedure works. The genetic material is put in the blastocyst, and is then absorbed by some of the cells there. Those cells can then (in theory) produce the proteins that the absorbed genes code for. So the mouse's brain might have some human protiens in it, but it would still be a mouses's brain.
Also, the Bishop's comment about a few human cells per organ being acceptable: not the way it works. As I said, there will be NO human cells, and the modified cells will come in patches. As a modified cell in the blastocyte divides, all it's progeny will have the modifications, so you'll end up with an area in the adult organism that has the modifications. Is it really too much to ask that the people who are trying to make these ethical decisions put in the effort to actually learn what they're talking about before passing judgment?
I believe the reference in the news blurb is to "The Island Of Doctor Moreau" by HG Wells. :)
'He was a dreamer, a thinker, a speculative philosopher... or, as his wife would have it, an idiot.' - Douglas Adams
this was a ref to the island of dr. moreau. irv weissman could reprise the role that brando more recently played. it wasn't meant seriously.
in truth, several similar things are done, but not approaching this scale, and not anything that would have the possibility (albeit remote) of creating offspring with cells that are entirely human.
Examples ...
(1) hybrids between murine (or other rodent species) and human cells. these experiments are typically done to map genetic factors unique to one organism or assay the recessive of dominant phenotypic nature of a gene factor. In long term culture, these are unstable. Mouse and human cells have different numbers of chromosomes which are duplicated at different speeds and move toward productive mitosis (somatic cell division) at different rates. The human chromosomes lag behind in the divisions and are eventually lost over time.
(2) immunologically crippled mice grafted with parts of the human immune system to study human immune function in an 'animal model'. These mice usually bearing the SCID or RAG genetic defect don't have an adaptive response/capability to recognize foreign cells as non-self. One popular model is the SCID-hu model in which mice typically are typically injected in their kidneys with human thymus, liver, and/or lymph node tissue in a capsule. There is partial immune reconstitution in these animals by the human immune system cells and they can be used in pathogen challenge or other studies. Obviously, potential progeny offspring would not genetically inherit human cells as a chimeric organism.
(3) Human genes can be introduced into mice as transgenes or by 'knock-ins' also more properly known as gene replacements. This is done to study human gene function in an animal context often looking at the cancer causing or cancer suppressing potential of genes of interest, the developmental role of particular genes, the immunological effect of genes, and more. These changes are very often heritable and there are many genetically altered mice currently available carrying numerous different human gene products
None of the examples above are on the scale of what is being considered in creating hybrid blastocysts between mouse and human. These are obviously most likely to be viable, but a concern I have is what happens when an enterprising individual takes it to the next level and successfully does the experiment using monkey (example was Rhesus) blastocysts ...what if human neurologic tissue is grafted
into this chimeric organism? This
type of research should not be taken out to an island run by a Dr. Moreau but
really needs to carefully considered before our science moves faster than our ability to comprehend
what we have created.
They already did, didn't you know ;-)
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and so did you!!!
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I'll have something intelligent to add one of these days...
It says:
Dipliod organisms (like all mammals including both humans and mice) have two sets of chromosomes and thus two copies of chromosome 1, two copies of chromosome 2, etc. Therefore if a particular mutation or altered gene is on, for example chromosome 3, then a mouse could have two copies of a normal chromosome (called a wild-type mouse), one normal and one altered chromosome (heterozygous), or two copies of the chromosome with the mutation (homozygous). Sometimes an animal homozygous for a certain mutation cannot survive to birth -- such a mutation is called "homozygous lethal." If the mutation is not homozygous lethal, and does not cause sterility, then one could raise a colony of mice that all have this particular mutation through selective breeding. The mice can then be examined to determine the phenotype -- or physical charactersitcs -- cause by the mutation.
and now the second sentence:
Whoever does this will have to use mice with no immune system othewise the mouse's immune system will recognise the embryonic stem cells that are introduced by the scientists as being forign and attack them. This is the same mechanism used by the body to fight off disease. (Translator's Comment: I dont think that is actualy true)
When you add the cells at the blastocyst stage, they are not absorbed; you are probably thinking of the proceedure at the ES stage, or how it's done with transgenics. This is more analagous to a knockout. The resultant animals will be chimeras; in the animal some cells will be like the host (the blastocyst) and some will be like the donor (the introduced cells). No cell will be a hybrid of the two. You can see this in the mice made for knockouts; donor cells are typically FVB's (white mice) and the hosts are C57's (black mice). The resultant animals are park C57 & part FVB. You can see it on the coat, it has black & white patches on it. (that's actually why you do it; you look for animals that have more white on them for breeding; more likely that they got the gene you altered)
There is a reason for everything. Sometimes that reason just sucks.